In Vitro and in Vivo (Mouse) Evaluation of Drug-Drug Interactions of Repaglinide with Anti-HIV Drugs

Vijay Saradhi Mettu¹, P. Yadagiri Swami^2*, P. Abigna², A. Ravinder Nath¹, Geeta Sharma³

¹Department of Pharmacy, University College of Technology, Osmania University, Hyderabad, India.
²Department of Chemistry, University College of Science, Osmania University, Hyderabad, India.
³Forma Therapeutics Singapore, Singapore City, Singapore.

DOI: 10.4236/pp.2015.64026                

Abstract

Repaglinide is type 2 short acting anti-diabetic drug which is primarily metabolized by CYP2C8 and CYP3A4 and is also a substrate of influx transporter OATP1B1. HIV drugs are potent inhibitors of CYP3A4 and OATP transporters. Several drug-drug interactions (DDIs) were noticed when protease inhibitors (PIs) coadministered with drugs metabolized by CYP3A4. The PIs are also potent mechanism based inhibitors, out which ritonavir is most potent. In the current study we evaluated in vitro (mouse and human liver microsomes) and in vivo DDIs of repaglinide with anti-HIV drugs. Out of the following tested drugs (Amprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Delavirdine, Maraviroc, Efavirenz, Nevirapine and Ketoconazole) Amprenavir (APV), Ritonavir (RTV) and Ketoconazole (KTZ) showed inhibition of OH-repaglinide formation in human and mouse liver microsomes. The positive reversible inhibitions were further tested for irreversible inhibitions where we didn’t observe any irreversible inhibitions. In vitro inhibitions were further evaluated in the in vivo pharmacokinetics (mouse) where repaglinide pharmacokinetics was altered by RTV and KTZ. The DDIs in both studies were very strong; the dose of repaglinide is reduced to 20 fold. In conclusion, there could be possible DDIs when RTV dosed with repaglinide; we have also demonstrated that mouse could be useful preclinical tool when used in conjunction with in vitro screening models for DDIs.

Keywords

Repaglinide, Drug-Drug Interaction, Repaglinide Km, Repaglinide Bioanalytical Method

Conflicts of Interest

The authors declare no conflicts of interest.

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